delta and delta androstene derivatives



United States Patent 2,883,325 A AND A ANDROSTENEDERIVATIVES Eugene J.Agnello and Gerald D. Laubach, Jackson Heights, N.Y., assignors to Chas.Pfizer & Co., Inc., Brooklyn, N.Y., a corporation of Delaware NoDrawing. Application September 4, 1958 Serial No. 758,915

8 Claims. (Cl. 167-65) CH: CH3

Z Y CH and the A1-, A and A -dehydro derivatives thereof wherein Y isS-hydroxyl or keto and Z is R is hydrogen or acyl hydrocarbon containingup to ten carbon atoms and Alk is an alkyl group containing up to threecarbon atoms.

A suitable compound for the preparation of the valuable therapeuticagents of this invention is 95,11B-oxido- A -androstene-3,17-dione. Thiscompound is represented by the formula It can be prepared from the knowncompound A -androstene-l1 8-hydroxyl-3,l7-dione by dehydration at the9(ll)-position, for example, with p-toluene sulfonic acid in refluxingbenzene or preferably with methyl sulfonyl chloride in pyridine toproduce the corresponding 9(ll)- unsaturated compound. In the preferredmethod, the starting compound is allowed to stand together with anexcess of methyl sulfonyl chloride in pyridine at a low temperature, forexample, to +5 C. for a period of from about 16 to 30 hours. Theintermediate mesylate compound can be isolated or alternatively the'reaction mixture can be refluxed, preferably in an inert atmosphere suchas nitrogen for a period of from about 1 to about 4 hours. The desiredcompound is isolated by evaporating the solvent in vacuo. The9(1l)-unsaturated compound resulting from this reaction is converted toa bromohydrin by treatment with, for example, N-bromoacetamide andperchloric acid in peroxide free dioxane according to known procedures.This compound is then converted to the 9(11)-epoxide by treatment withpotassium acetate.

A double bond can be introduced at the 1-position in accordance with theprocedure described in earlier filed patent application Serial No.526,786, filed August 5, 1955, now abandoned, by contacting the selectedcompound with selenium dioxide.

In this earlier filed application a method is described whereby a doublebond can be introduced at the 1(2)-position of a A -3-keto steroid bycontacting it with selenium dioxide in an inert organic solvent at anelevated temperature. Solvents which are useful for this reactioninclude, for example, tert-butanol, tert-pentanol, benzene, ethyleneglycol diethers, such as dibutyl Cellosolve; diproyl ether; ethyleneglycol and various other glycol ethers; phenetole; xylene; dioxane;naphthalene and others. Preferred conditions include the addition of alower aliphatic acid, particularly acetic acid to a tert-butanolmixture. In carrying out the reaction it is generally preferred toutilize temperatures of from about C. to about 200 C. for from about onehour to about one hundred hours. Generally several molecular proportionsof selenium dioxide are added during the reaction period. Theapplication of this reaction to the preparation of the valuablecompounds of the instant invention is more fully illustrated in theappended examples.

A A -dehydro9,8,11[i-oxido starting material for the preparation of theA -dehydro derivatives of this invention can be prepared from the A-9fi,l1B-oxido compound prepared as described above -by application ofthe reactions set forth in earlier filed patent applications, Serial No.526,554, filed August 4, 1955, and Serial No. 633,538,- filed January10, 1957. These applications describe the method for the introduction ofdouble bonds at the 6(7)- position by dehydrogenation of a3-keto-6-dihydro-A steroid compound with a quinone having anoxidationreduction potential less than 0.5 at a temperature of between70 C. and C. in an inert organic solvent having a boiling point of atleast about 70 C. These solvents include mono-nuclear aromatichydrocarbons, mono-nuclear halogenated aromatic hydrocarbon solvents,oxygenated polar alicyclic organic solvents and oxygenated polaraliphatic organic solvents. Typical solvents include tertiary 'butanol,n-amyl alcohol, hexanol, isoamyl alcohol, heptano1-3, cyclohexanol,ortho-dichlorobenzene, xylene, tertiary amyl alcohol, secondary amylalcohol, benzene, toluene, acetic acid, propionic acid, butyric acid,butyl acetate, amyl acetate, hexyl acetate, butyl propionate, propylpropionate and amyl pr-opionate. The preparation of the valuablecompounds of the instant invention using the process described in theearlier filed applications is more fully illustrated in the appendedexamples.

For the preparation of the A -dehydro derivatives of this invention, itis not critical whether the double bond is introduced first at the6-position and then at the 1-position or vice versa. Better yields ofproduct are" generally obtained by first introducing the double bond atthe 6-position. I

Various modifications at the C position can be made by procedures wellknown in the art. For conversion of the l7-keto group to a 17-hydroxygroup the 3-keto group is preferentially converted to a pyrrolidinylderivative, the 17-keto group is then reduced with lithium aluminumhydride and the pyrrolidinyl'group removed by refluxing in a sodiumacetate-acetic acid buffered aqueousmethanol solution. This reaction isdescribed in detail by Heyl and Herr in the Journal of the AmericanChemical Society, 75, 1918 (1953). The vinyl group can be introduced atthe C position by treating the 17-ketone with acetylene in the presenceof a potassium tert-alkoxide (for example, potassium tert-amyl alkoxide)and reducing the thus produced ethynyl group by catalytic hydrogenation.For the introduction of the vinyl group the 3-keto group should again beprotected by a pyrrolidinyl group which is, of course, subsequentlyremoved. The l7-keto group can be converted to a tertiary alcohol, thatis, an alkyl and hydroxyl group can be introduced at the 17-position bytreatment with an organo-metallic compound of the type RLi or RMgXwherein R is alkyl up to four and X is a halogen. For the introductionof the vinyl group or the reaction with an organo-metallic compound the3-keto group should be protected by a pyrrolidinyl group as describedabove. A 17-hydroxyl group can be readily esterified with the usualesterifying agents if it is the hydroxyl group of a secondary alcohol.If it is the hydroxyl of a tertiary alcohol it can be esterified byrefluxing in a liquid anhydride, for example, acetic or propionicanhydride or the case of a solid anhydride by heating the compound atabout 100 C. in a hydrocarbon solvent solution such as xylene containingthe anhydride and catalytic amounts of potassium acetate. Esters andacid esters of the l7-hydroxyl group can be obtained in this manner. Anl1/3-hydroxyl group can be converted to a keto group by oxidation, forexample, with chromic acid. If, however, there is a secondary hydroxylgroup at the l7-posititon, it is best to acylate this group beforeoxidizing this group at the ll-position. As stated above, all of thesereactions are conventional in the art.

A 9,8,11fi-oxide is converted to a A -compound of this invention inaccordance with the procedure set forth by Wendler et al. in the Journalof the American Chemical Society, 79, page 4476. In this publication, amethod is described for converting the oxide to a A -11-hyclroxycompound using perchloric acid. The reaction can be carried out in analcohol free hydrocarbon or halogenated hydrocarbon solvent such aspetroleum ether, benzene, chloro benzene, toluene, ethylene dichloride,chloroform or carbon tetrachloride at a temperature of from about toabout 10 C. during a period of from about 2 to about 25 minutes using atleast an equivalent quantity of 60% perchloric acid. An excess ofperchloric acid as high as 200% can be used to ensure complete reaction.

The desired product is isolated by diluting the reaction mixture withfrom 1 to 3 times its volume of ice cold water. The resulting aqueousmixture is extracted with a suitable solvent, for example, chloroform ora mixture of chloroform in ethyl acetate. The organic solution is driedover an anhydrous drying agent such as sodium or magnesium sulfate, thedrying agent removed and the desired product isolated by evaporation ofthe solvent preferably in vacuo. The product may be purified bytriturating with a 1:1 mixture of ethyl acetate and ether followed byrecrystallization from ethyl acetate.

A A -compound of this invention is converted by isomerization to a A-compound within the purview of this invention. The isomerization stepcan be carried out by treatment with an alkaline reagent in an alkanolsolvent, for example, dilute sodium or potassium hydroxide in methanolor ethanol. The reaction is performed at room temperature, that is, fromabout 20 C. to about 30 C. For optimum results, an inert atmosphere, forexample, a nitrogen atmosphere is preferred. At the end of the reactionperiod which may be from about to about 30 minutes, the reaction mixtureis made slightly acid by the addition of an organic acid, for example,acetic acid. The product is isolated by evaporation of the solvent andpurified by trituration with water. The procedure is fully illustratedin the appended examples.

An llfi-hydroxyl compound of this invention is converted to the valuablell-keto compound by oxidation. The oxidative step may be performedbefore or after isomerization. There are a number of reagents availablefor this oxidation and these include, for example, chromium dioxide,sodium dichromate, the chromic acid-pyridine complex, N-bromoacetamideand aluminum isopropoxide or aluminum tert-bu oxide in the pr nce of ahydrogen acceptor such as acetone or cyclohexanone in an inert organicsolvent such as benzene, toluene or xylene.

Although the reactions described are applicable to compounds in whichthe 17-position carries a free B-hydroxyl group, for optimum results, itis best that this hydroxyl group be acylated with an acyl hydrocarbongroup containing up to ten carbon atoms. The term acyl hydrocarbonincludes acyl hydrocarbon groups containing only carbon, hydrogen andoxygen derived from monocarboxylic or dicarboxylic acids. In the eventthat the acyl hydrocarbon group is one derived from a dicarboxylic acid,it is often advantageous to treat the isolated therapeutically activecompound with a base derived from an alkali metal or alkaline earthmetal to prepare a metal salt. These bases include, for example, sodium,potassium, barium and calcium hydroxide as well as the correspondingcarbonates and bicarbonates. Products so prepared are especially usefulbecause of their increased solubility in water.

The products of this invention as stated above are valuable medicinalagents being particularly useful for their anabolic activity, that is,for their aid in rebuilding human tissue injured by surgery or depletedby serious illness. When used in the treatment of these conditions thecompounds of this invention are administered in dosages of aproximatelythe same order of magnitude as other agents often recommended for thesepurposes such as 17a-ethyl- 17-hydroxy nor androsterone; 11fi,17;3dihydroxy-9txfiuoro-lh-methyl 4 androstene 3 one or 1113,1713-dihydroxy-l7a-methyl-4-androstene 3 one. Because of their high order ofactivity, it is sometimes possible to use dosages of the compounds ofthis invention which are lower than compounds presently utilized. Theyaccomplish their valuable therapeutic effect with a minimum ofundesirable androgenic activity. For this reason, and because they areeffective at relatively low levels, they can be administered forextended periods of time to patients of either sex.

The biologically active compounds of this invention may be administeredalone or in combination with acceptable pharmaceutical carriers, thechoice of which is determined by the preferred route of administration,the solubility of the compound and standard pharmaceutical practice. Fororal administration the compounds may be administered in the form oftablets containing excipients such as starch or milk sugar. Aqueoussolutions and elixirs which may be sweetened or flavored may also beemployed. For intra-articular injection aqueous suspensions may be used.In this case various suspending and wetting agents may be added to thecomposition to obtain a suspension not tending to settle out easily orto pack down in the bottle in which it is stored. Intramuscular andsubcutaneous dosage forms may also be prepared by standardpharmaceutical practice.

The following examples are given solely for the purpose of illustrationand are not to be construed as limitations of this invention, manyapparent variations of which are possible without departing from thespirit or scope thereof.

EXAMPLE I A -androstadiene-3,17-di0ne A solution containing 3 ml. ofpyridine and 0.5 ml. of methylsulfonyl chloride together with 240 mg. ofA androstene-11[3-ol-3,17-dione was maintained at a temperature of 0 C.for 24 hours. At the end of this period a small amount of ice and waterwas added and the resulting mixture extracted with ethyl acetate. Theorganic layer was separated and washed successively with equal volumesof water, 2 N hydrochloric acid and again with water. It wasconcentrated to dryness to leave 11/8- mesylate as a residue. Theresidue was dissolved in 3 m1. of pyridine and the solution refluxed ina nitrogen atmosphere for two hours. The resulting solution wasextracted with ethyl acetate, the organic layer Washed as gas es EXAMPLEII 9u-bromo-A -androstene-1Idol-3,1 7-dione To a suspension containing2.4 g. of the compound prepared as described in the previous example in20 ml. of pure peroxide-free dioxane' and 3.65 ml. of 0.46 N perchloricacid there was added in the dark at room temperature with stirringduring a one hour period a total of 1.14 g. of N-bromoacetamide. At theend of two hours, all of the starting material had. dissolved and 2.5ml. of sodium sulfate solution was added with stirring. A few grams ofice in. 20 ml. of chloroform was added and the layers separated. Theorganic layer was washed twice with water while maintaining thetemperature at about 20 C. by the occasional addition of ice. Theorganic solution was concentrated in vacuo and triturated with acetone.The mixture was maintained at a temperature of about 5 C. and thedesired product recovered by filtration.

EXAMPLE III A solution of 2.3 g. of the compound prepared in theprevious example in 75 ml. of dioxane was added to a solution of 15.8 g.of anhydrous potassium acetate in 160 ml. of absolute alcohol at atemperature just below the reflux temperature of the alcohol solution.The mix ture was brought to reflux within three minutes and the reactionallowed to proceed for a total of forty minutes. After cooling in an icebath, 400 ml. of ice water was added with stirring and the desiredproduct precipitated.- Successive crops of the desired product wereobtained by concentrating the mother liquor.

EXAMPLE IV 9,8,11 ii-oxido-A -andrstadiene-3,1 7-di0ne A mixturecontaining 808 mg. of the compound prepared in the previous example and900 mg. of chloranil in 72 ml. of xylene was refluxed under a nitrogenatmosphere for eighteen hours. The reaction mixture was then dilutedwith 150 m1. of chloroform. The reaction mixture was washed with severalsmall portions of 5% sodium hydroxide solution and then with water. Itwas dried over anhydrous sodium sulfate for several hours. The mixturewas filtered, concentrated under vacuum and the residue triturated withether to obtain the desired product.

EXAMPLE V 95,] lfi-oxia o-A -a ndr0statriene-3J 7 -di0ne A mixturecontaining 0.140 g. of the compound of Example IV and 0.15 ml. ofglacial acetic acid in 15 ml. of tert-butanol was prepared; 0.086 g. ofselenium dioxide was added and the mixture was refluxed in a nitrogenatmosphere for 2% hours. An additional 0.86 g. of selenium dioxide wasadded and the mixture refluxed an additional four hours. The mixture wasfiltered and the filtrate evaporated to dryness in vacuo. The residuewas taken up in 25 m1. of ethyl acetate and washed successively with 5ml. of water, twice with 4 ml. portions of 5% potassium bicarbonate,once with 5 ml. of water, twice with 5 ml. portions of ice cold 15%ammonium sulfide, once with 5 ml. of cold 2N ammonium. hydroxide, onceWith 5 ml. of water, once with 2N aqueous hydrochloric acid, and finallytwice with 5 ml. portions of water. The layers were separated and theorganic layer dried over anhydrous sodium sulfate. The mixturewasfiltered and evaporated to dryness in vacuo. The residue wastriturated in ethyl ether-ethyl acetate to give the desired product incrystalline form.

918,11/3-oxido-A -androstadiene-3,17-dione was similarly prepared fromthe product of Example III.

6 EXAMPLE VI A -androstadiene-11 5-01-31] 7-di0ne A mixture was preparedcontaining eight g. of the product obtained in Example III in 80 ml. ofethanol-free chloroform and the mixture was added dropwise to 20 ml. ofice cold 60% perchloric acid for a period of two minutes whilemaintaining the temperature below 5 C. After stirring for an additional15 minutes, the solution was diluted with 200 ml. of ice water. Thelayers were separated and the aqueous layer extracted twice with 2:1chloroform-ethyl acetate. The combined solvent layers were washed freeof acid with water, dried over anhydrous sodium sulfate, filtered andthe filtrate distilled in vacuo. The residue Was taken up in ml. ofchloroform and refluxed for ten minutes. The hot mixture was dilutedwith 175 ml. of benzene, cooled to room temperature and filtered. Theproduct was triturated with 1: 1 ethyl acetateether and dried in vacuoto give the desired product.

A -androstatriene-115-ol-3,17-dione and the corresponding A and A-6-dihydro compounds are similarly prepared from the products ofExamples IV and V.

EXAMPLE VII A -andr0stadiene-1118-013,] 7-a'z'one A total of 200 mg. ofthe 11 product prepared in accordance with the previous example isstirred in 20 ml. of 0.005 N potassium hydroxide in ethanol for tenminutes. The solution is made slightly acidic by the addition of 10%aqueous acetic acid. The reaction mixture is evaporated to dryness invacuo and the residue triturated with water to give the desired product.

A -androstatriene-1l 3-ol-3,17-dione and the corresponding A and A-G-dihydro compounds are similarly prepared from the compounds of theprevious example.

EXAMPLE VIII Chromic anhydride (0.125 g.) was added to fifteen ml. ofcold pyridine at about 5 C. and the mixture allowed to warmspontaneously to room temperature. To this solution was added 2.5 g. ofthe A product prepared in accordance with Example VI in 20 m1. ofpyridine and the mixture was allowed to stand at room temperature for 24hours. The excess pyridine was first neutralized with 5% aqueoushydrochloric acid and the mixture extracted with ether. The etherextract was dried over anhydrous sodium sulfate, filtered and thedesired product obtained by removing the solvent in vacuo.

The following compounds are similarly prepared using the appropriatestarting compounds obtained as described in the previous examples.

A -androstatetraene-3 ,1 1,17-trione A -androstatriene-3,11,17-trione A-androstatetraene-3, 1 1,17-trione A -androstatriene-3,1 1,17-trione A-androstadiene-3J 1,17-trione A -androstatriene-3,1 1,17-trione EXAMPLEIX starting compounds obtained by the procedures of the previousexamples.

EXAMPLE X This compound as well as A -androstatriene-l1fi,l7}3-dio1-3-one, the corresponding N -compound and the A -6-dihydro compoundwere prepared using the procedure of Example VII on the appropriatestarting compounds prepared in accordance with the previous examples.

EXAMPLE XI 1 7u-methyl-A -androstadiene-l 1 5,1 7B-diol-3-0ne EXAMPLEXII 17a-methyl-A -andrstadiene-115,1 7B-di0l-3-0ne This compound and thecorresponding Hot-methyl- M -androstatriene-l15,17B-diol-3-one, the A-com pound and the A -6 dihydro compound were each prepared using theprocedure of Example VII on the appropriate starting compounds.

The corresponding 17a-methyl and 17oa-propyl compounds were similarlyprepared.

EXAMPLE XIII 1 7a-ethynyl-A -andr0stadiene-113,1 7B-di0l-3-0ne Thiscompound was prepared by reacting A -androstadiene-llB-ol-3,17-dione inaccordance with known procedures with acetylene in the presence ofpotassium tert-amyl alkoxide after first protecting the 3-keto groupwith a pyrrolidinyl moiety which is in turn removed subsequent to thereaction with acetylene.

The compound l7a-ethynyl-A androstatriene- 11/8,l7 3-diol-3-one, thecorresponding A compound and the A -6-dihydro compound is similarlyprepared.

EXAMPLE XIV 1 7a-ethynyl-d -androstadiene-l149,17fl-di0l-3-0ne Thiscompound as well as l7a-ethynyl-A androstatrienc-IIfiJWS-diol 3 one, thecorresponding A compound and the A -6-dihydro compound were eachprepared using the procedure of Example VII with the appropriatestarting materials.

EXAMPLE XV 17u-vinyl-A -andr0stadiene-]1;8,1 75-di0l-3-0ne This compoundas well as 17oc-vinyl-A -a ndrostatriene-ll[3,l7fi-diol 3 one, thecorresponding A compound and the A -6-dihydro compound were eachprepared by reduction of the appropriate starting materials in thepresence of a palladium catalyst by known procedures.

EXAMPLE XVI 17a-vinyl-A -arzdr0stadieneI1,8,1 7/3-diol-3-one Thiscompound as well as 17ot-viny1-A androstatriene-l1fl,l7;8-diol 3 one,the corresponding A compound and the A -6-dihydro compound were eachprepared using the procedure of Example VII and the appropriate startingmaterials.

EXAMPLE XVII A variety of 17 esters of the free alcohols prepared asdescribed in the previous examples Were each prepared by acylation usingconventional methods. The compounds prepared include formates, acetates,propanoates, propenoates, isobutyrates, hexanoates, benzonoates,octanoates, decanoates, hemisuccinates, trimethyl acetates,cyclopentylpropionates, etc. The acid esters of dicarboxylic acids suchas the hemisuccinate have the advantage that alkali metal salts andalkalin earth metal salts can be prepared firom them by treatment withmolar proportions of a base such as sodium or potassium bicarbonate orbarium hydroxide. These salts are water soluble, an advantage notpossessed by the free alcohols themselves or by ordinary esters thereof.

EXAMPLE XVIII The procedure of Example VIII was used to prepare thell-keto compounds corresponding to the 1113- ols prepared in accordancewith the procedures of the previous examples. Compounds containing afree hydroxyl group at the l7B-position were first converted to thecorresponding acetates. The following compounds were prepared:

9a-bromo-A -androstene-3, l 1, l7-trione A -androstadiene-3,11,17-trioneA -androstatriene-3,1 1,17-trione A -androstadiene-3 ,l 1,17-trione A-androstatriene-3,1 1,17-trione a -androstadiene 17fl-ol-3,11-dione17-acetate M' -androstatriene-1713-01-11l-dione l7-acetate M-androstatriene-l7B-ol-3, 1 l-dione 17-acetate A-andrQstadiene-l75-01-3, 1 l-dione l7-acetate A-androstatriene-17,8-01-3,1l-dione l7-acetate l7a-methyl-Mandrostadiene-17B-ol-3,11 dione 17- acetate l7a-rnethyl-A-androstatriene l7B-ol-3,ll dione l7-acetate l7a-methyl-A -androstadiencl7fi-ol-3,ll dione 17- acetate l7ot-methyl-A androstatriene17/3-ol-3,11-dione 17- acetate 17a-ethynyl-A -androstadiene-l7fl-ol-3,11dione l7- acetate l7oc-ethynyl-A -androstatriene-l7;3-ol-3,1l-dione 17acetate.

l7a-ethynyl-M -androstadiene-1713-01 3,11 dione 17- acetatel7u-ethynyl-A androstatriene--01 3,11 dione 17- acetate l7m-vinyl-A-andnostadiene 17l8-ol-3,11 dione l7- acetate 17a vinyl 13451894)androstatriene-Up ol 3,11-

dione l7-acetate 17a vinyl A androstadiene 175 ol 3,11 dione 17-'acetate17a vinyl A4518 androstatriene 173 ol 3,11 dione 17-acetate Double bondsare introduced at the 6-position using chloranil and at the l-positionusing selenium dioxide in accordance with the procedures of Examples IVand V to prepare A compounds and A -6-dihydro compounds corresponding tothose in the above list.

The procedure of Example VIII was also used to prepare the 17OL-Cthyland l7u-propyl compounds corresponding to the 17a-methy1 compounds ofthe above list.

The acetate esters were converted to the corresponding free alcohols byalkaline hydrolysis, using conventional methods and these in turn wereconverted to those esters other than the acetate listed in Example XVII.

9 What is claimed is: 1. A compound selected from the group consistingof those having the formulas 0Ha cm 5 Y z Y z 0H3 on, J

and the A ,A and A -dehydro derivatives thereof wherein Y is selectedfrom the group consisting of keto and fl-hydroxyl and Z is selected fromthe group consisting of 16 R is selected from the group consisting ofhydrogen and acyl hydrocarbon containing up to ten carbon atoms and Alkis selected from the group consisting of alkyl groups containing up tothree carbon atoms.

2. A pharmaceutical composition comprising a compound as claimed inclaim 1 together with a pharmaceutically acceptable carrier.

3. A -androstadiene-11fl-ol-3,17-dione.

. A -androstatriene-1 1;9-ol-3,17-dione.

. A -androstatetraene-1lp-ol-3,l7-dione. A -androstadiene-1 15-01-3,17-dione.

. A -androstatriene-1 1,6-01-3, 17-dione.

. A -androstatetraene-1 1 5-013, 17 -dione.

No references cited.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent5100258833325 April 21, 1959 Eugene J. Agnello et a1.

11 the -printed specification It is herebfi certified that error appearsi of the above numbered patent requiring correction and that the saidLetters Patent should read as corrected below.

line 26, Example XII, for "hydroxy" read dihydro Signed and sealed this3rd day of jblowember 1959.

(SEAL) Attest:

KARL E, AXLINE ROBERT c. WATSON Commissioner of Patents AttestingOfficer

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THE FORMULAS
 2. A PHARMACEUTICAL COMPOSITION COMPRISING A COMPOUND AS CLAIMED IN CLAIM 1 TOGETHER WITH A PHARMACEUTICALLY ACCEPTABLE CARRIER. 